System Toxicity and Risk Assessment
A.Y. 2024/2025
Learning objectives
The course aims to provide the methodological knowledge and the skills necessary to apply the current methodologies and guidelines for risk assessment for humans from exposure to chemicals, particular attention is paid to the application of European Regulations.
The training course allows students to acquire competences in the evaluation of toxicological databases of xenobiotics and biotechnological products and to reach a risk assessment based on scientific principles and methodological approaches shared internationally, in order to provide quantitative values for safe use.
The training course allows students to acquire competences in the evaluation of toxicological databases of xenobiotics and biotechnological products and to reach a risk assessment based on scientific principles and methodological approaches shared internationally, in order to provide quantitative values for safe use.
Expected learning outcomes
Autonomy of the students in consulting a toxicological database, to extrapolate the health-based guidance values and apply them to different types of products (pesticides, cosmetics, drugs, etc.), to define the safe conditions of use for humans.
Lesson period: First semester
Assessment methods: Esame
Assessment result: voto verbalizzato in trentesimi
Single course
This course can be attended as a single course.
Course syllabus and organization
Single session
Responsible
Lesson period
First semester
Course syllabus
Risk assessment: objectives and tools
Health based guidance values. NOAEL, UF and ADI (+3 h tutorials)
Threshold of toxicological concern (+ 2 h tutorial)
Benchmark dose: meaning and applications (+2 h tutorials)
Carcinogen evaluation: margin of exposure
Pesticide dossier
Cosmetic dossier: Margin of safety and Systemic exposure dosage
Safety of Homeopathic drugs (+ 3 h tutorials)
Botanicals
Acute toxicity: impact on labelling
Non-intentionally added substances
Drug development-pre-clinical experiments (+ 2 h tutorials)
Cumulative risk assessment (+2 h tutorials)
Integration of Mechanism of action in risk assessment
NAM: Adverse outcome pathway (+ 2 h tutorials)
Health based guidance values. NOAEL, UF and ADI (+3 h tutorials)
Threshold of toxicological concern (+ 2 h tutorial)
Benchmark dose: meaning and applications (+2 h tutorials)
Carcinogen evaluation: margin of exposure
Pesticide dossier
Cosmetic dossier: Margin of safety and Systemic exposure dosage
Safety of Homeopathic drugs (+ 3 h tutorials)
Botanicals
Acute toxicity: impact on labelling
Non-intentionally added substances
Drug development-pre-clinical experiments (+ 2 h tutorials)
Cumulative risk assessment (+2 h tutorials)
Integration of Mechanism of action in risk assessment
NAM: Adverse outcome pathway (+ 2 h tutorials)
Prerequisites for admission
Requirements :
The course requires knowledge of biology, physiology, chemistry and toxicology.
The course requires knowledge of biology, physiology, chemistry and toxicology.
Teaching methods
The course includes lectures and tutorials on specific topics that will be treated during the exam.
Teaching Resources
UPDATED GUIDELINES AND REGULATION concerning HUMAN SAFETY from EU Agencies (ECHA; EMA; EFSA; SCCS, SCHENIR, etc..), International Agencies (FDA, EPA, IARC)
Hazard identification by methods of animal-based toxicology. Barlow SM, Greig JB, Bridges JW, Carere A, Carpy AJ, Galli CL, Kleiner J, Knudsen I, Koëter HB, Levy LS, Madsen C, Mayer S, Narbonne JF, Pfannkuch F, Prodanchuk MG, Smith MR, Steinberg P. Food Chem Toxicol. 2002 Feb-Mar;40(2-3):145-91.
Update: Guidance on the use of the benchmark dose approach in risk assessment. EFSA Scientific Committee, Hardy A, Benford D, Halldorsson T, Jeger MJ,Knutsen KH, More S, Mortensen A, Naegeli H, Noteborn H, Ockleford C, Ricci A, Rychen G, Silano V, Solecki R, Turck D, Aerts M, Bodin L, Davis A, Edler L, Gundert-Remy U, Sand S, Slob W, Bottex B, Abrahantes JC, Marques DC, Kass G and Schlatter JR, 2017.
EFSA Journal 2017;15(1):4658, 41 pp. doi:10.2903/j.efsa.2017.4658
Scientific Opinion on the guidance on the use of the weight of evidence approach in scientific
assessments. EFSA Scientific Committee, Hardy A, Benford D, Halldorsson T, Jeger MJ,
Knutsen HK, More S, Naegeli H, Noteborn H, Ockleford C, Ricci A, Rychen G, Schlatter JR, Silano V,
Solecki R, Turck D, Benfenati E, Chaudhry QM, Craig P, Frampton G, Greiner M, Hart A, Hogstrand C,
Lambre C, Luttik R, Makowski D, Siani A, Wahlstroem H, Aguilera J, Dorne J-L, Fernandez Dumont A,
Hempen M, Valtue~na Mart ınez S, Martino L, Smeraldi C, Terron A, Georgiadis N and Younes M, 2017.
EFSA Journal 2017;15(8):4971, 69 pp. https://doi.org/10.2903/j.efsa.2017.4971
EMA/CHMP/ CVMP/ SWP/169430/2012 Committee for Medicinal Products for Human Use (CHMP), Committee for Medicinal Products for Veterinary Use (CVMP), Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities, 20 November 2014
7199/VI/99 rev. 5 05/07/2001 Draft Guidance Document GUIDANCE FOR THE SETTING OF AN ACUTE REFERENCE DOSE (ARfD)
International Programme on Chemical Safety & IPCS Workshop on Incorporating Uncertainty and Variability into Risk Assessment (2000 : Berlin, Germany). (2005). Chemical-specific adjustment factors for interspecies differences and human variability : guidance document for use of data in dose/concentration-response assessment. World Health Organization. https://apps.who.int/iris/handle/10665/43294
TR 085 - Recognition of, and Differentiation between, Adverse and Non-adverse Effects in Toxicology Studies
29 December 2002
TR 110 : Guidance on Assessment Factors to Derive a DNEL | Dec 2010 Executive Summary The European Regulation on the Registration, Evaluation, Authorisation
CHMP/ICH/83812/2013 Committee for Human Medicinal ProductsICH guideline M7(R1)on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk, 25 August 2015EMA
OPEN LITERATURE
Virunya S. Bhat, M.E. (Bette) Meek, Mathieu Valcke, Caroline English, Alan Boobis & Richard Brown (2017) Evolution of chemical-specific adjustment factors (CSAF) based on recent international experience; increasing utility and facilitating regulatory acceptance, Critical Reviews in Toxicology, 47:9, 733-753, DOI: 10.1080/10408444.2017.1303818
Is it adverse, non-adverse, adaptive or artifact?
Arun R. Pandiri, Roy L. Kerlin, Peter C. Mann, Nancy E. Everds4, Alok K. Sharma, L. Peyton Myers, and Thomas J. Steinbach
Toxicol Pathol. 2017 January ; 45(1): 238-247. doi:10.1177/0192623316672352
Current concepts on integrative safety assessment of active substances of botanical, mineral or chemical origin in homeopathic medicinal products within the European regulatory framework.
Buchholzer ML, Werner C, Knoess W.
Regul Toxicol Pharmacol. 2014 Mar;68(2):193-200. doi: 10.1016/j.yrtph.2013.12.008. Epub 2013 Dec 30.
What determines the acceptability of genetically modified food that can improve human nutrition?
Purchase IF. Toxicol Appl Pharmacol. 2005 Sep 1;207(2 Suppl):19-27.
Scientific analysis of the proposed uses of the T25 dose descriptor in chemical carcinogen regulation.
Roberts RA, Crump KS, Lutz WK, Wiegand HJ, Williams GM, Harrison PT, Purchase IF.
Arch Toxicol. 2001 Nov;75(9):507-12.
Safety assessment of botanicals and botanical preparations used as ingredients in food supplements: testing an European Food Safety Authority-tiered approach.
Speijers G, Bottex B, Dusemund B, Lugasi A, Tóth J, Amberg-Müller J, Galli CL, Silano V, Rietjens IM.
Mol Nutr Food Res. 2010 Feb;54(2):175-85. doi: 10.1002/mnfr.200900240.
Application of the TTC concept to unknown substances found in analysis of foods.
Koster S, Boobis AR, Cubberley R, Hollnagel HM, Richling E, Wildemann T, Würtzen G, Galli CL.
Food Chem Toxicol. 2011 Aug;49(8):1643-60. doi: 10.1016/j.fct.2011.03.049. Epub 2011 Mar 30
A tiered approach to systemic toxicity testing for agricultural chemical safety assessment.
Doe JE, et al. Crit Rev Toxicol. 2006 Jan;36(1):37-68.
A proposed framework for assessing risk from less-than-lifetime exposures to carcinogens.
Felter SP et al.
Crit Rev Toxicol. 2011 Jul;41(6):507-44. doi: 10.3109/10408444.2011.552063. Epub 2011 May 18
Risk assessment in the 21st century: roadmap and matrix.
Embry MR et al. Crit Rev Toxicol. 2014 Aug;44 Suppl 3:6-16. doi: 10.3109/10408444.2014.931924.
The use of mode of action information in risk assessment: quantitative key events/dose-response framework for modeling the dose-response for key events.
Simon TW et al. Crit Rev Toxicol. 2014 Aug;44 Suppl 3:17-43. doi: 10.3109/10408444.2014.931925.
Regulatory assessment of chemical mixtures: Requirements, current approaches and future perspectives.
Kienzler A, Bopp SK, van der Linden S, Berggren E, Worth A.
Regul Toxicol Pharmacol. 2016 Oct;80:321-34. doi: 10.1016/j.yrtph.2016.05.020. Epub 2016 May 20
Hazard identification by methods of animal-based toxicology. Barlow SM, Greig JB, Bridges JW, Carere A, Carpy AJ, Galli CL, Kleiner J, Knudsen I, Koëter HB, Levy LS, Madsen C, Mayer S, Narbonne JF, Pfannkuch F, Prodanchuk MG, Smith MR, Steinberg P. Food Chem Toxicol. 2002 Feb-Mar;40(2-3):145-91.
Update: Guidance on the use of the benchmark dose approach in risk assessment. EFSA Scientific Committee, Hardy A, Benford D, Halldorsson T, Jeger MJ,Knutsen KH, More S, Mortensen A, Naegeli H, Noteborn H, Ockleford C, Ricci A, Rychen G, Silano V, Solecki R, Turck D, Aerts M, Bodin L, Davis A, Edler L, Gundert-Remy U, Sand S, Slob W, Bottex B, Abrahantes JC, Marques DC, Kass G and Schlatter JR, 2017.
EFSA Journal 2017;15(1):4658, 41 pp. doi:10.2903/j.efsa.2017.4658
Scientific Opinion on the guidance on the use of the weight of evidence approach in scientific
assessments. EFSA Scientific Committee, Hardy A, Benford D, Halldorsson T, Jeger MJ,
Knutsen HK, More S, Naegeli H, Noteborn H, Ockleford C, Ricci A, Rychen G, Schlatter JR, Silano V,
Solecki R, Turck D, Benfenati E, Chaudhry QM, Craig P, Frampton G, Greiner M, Hart A, Hogstrand C,
Lambre C, Luttik R, Makowski D, Siani A, Wahlstroem H, Aguilera J, Dorne J-L, Fernandez Dumont A,
Hempen M, Valtue~na Mart ınez S, Martino L, Smeraldi C, Terron A, Georgiadis N and Younes M, 2017.
EFSA Journal 2017;15(8):4971, 69 pp. https://doi.org/10.2903/j.efsa.2017.4971
EMA/CHMP/ CVMP/ SWP/169430/2012 Committee for Medicinal Products for Human Use (CHMP), Committee for Medicinal Products for Veterinary Use (CVMP), Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities, 20 November 2014
7199/VI/99 rev. 5 05/07/2001 Draft Guidance Document GUIDANCE FOR THE SETTING OF AN ACUTE REFERENCE DOSE (ARfD)
International Programme on Chemical Safety & IPCS Workshop on Incorporating Uncertainty and Variability into Risk Assessment (2000 : Berlin, Germany). (2005). Chemical-specific adjustment factors for interspecies differences and human variability : guidance document for use of data in dose/concentration-response assessment. World Health Organization. https://apps.who.int/iris/handle/10665/43294
TR 085 - Recognition of, and Differentiation between, Adverse and Non-adverse Effects in Toxicology Studies
29 December 2002
TR 110 : Guidance on Assessment Factors to Derive a DNEL | Dec 2010 Executive Summary The European Regulation on the Registration, Evaluation, Authorisation
CHMP/ICH/83812/2013 Committee for Human Medicinal ProductsICH guideline M7(R1)on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk, 25 August 2015EMA
OPEN LITERATURE
Virunya S. Bhat, M.E. (Bette) Meek, Mathieu Valcke, Caroline English, Alan Boobis & Richard Brown (2017) Evolution of chemical-specific adjustment factors (CSAF) based on recent international experience; increasing utility and facilitating regulatory acceptance, Critical Reviews in Toxicology, 47:9, 733-753, DOI: 10.1080/10408444.2017.1303818
Is it adverse, non-adverse, adaptive or artifact?
Arun R. Pandiri, Roy L. Kerlin, Peter C. Mann, Nancy E. Everds4, Alok K. Sharma, L. Peyton Myers, and Thomas J. Steinbach
Toxicol Pathol. 2017 January ; 45(1): 238-247. doi:10.1177/0192623316672352
Current concepts on integrative safety assessment of active substances of botanical, mineral or chemical origin in homeopathic medicinal products within the European regulatory framework.
Buchholzer ML, Werner C, Knoess W.
Regul Toxicol Pharmacol. 2014 Mar;68(2):193-200. doi: 10.1016/j.yrtph.2013.12.008. Epub 2013 Dec 30.
What determines the acceptability of genetically modified food that can improve human nutrition?
Purchase IF. Toxicol Appl Pharmacol. 2005 Sep 1;207(2 Suppl):19-27.
Scientific analysis of the proposed uses of the T25 dose descriptor in chemical carcinogen regulation.
Roberts RA, Crump KS, Lutz WK, Wiegand HJ, Williams GM, Harrison PT, Purchase IF.
Arch Toxicol. 2001 Nov;75(9):507-12.
Safety assessment of botanicals and botanical preparations used as ingredients in food supplements: testing an European Food Safety Authority-tiered approach.
Speijers G, Bottex B, Dusemund B, Lugasi A, Tóth J, Amberg-Müller J, Galli CL, Silano V, Rietjens IM.
Mol Nutr Food Res. 2010 Feb;54(2):175-85. doi: 10.1002/mnfr.200900240.
Application of the TTC concept to unknown substances found in analysis of foods.
Koster S, Boobis AR, Cubberley R, Hollnagel HM, Richling E, Wildemann T, Würtzen G, Galli CL.
Food Chem Toxicol. 2011 Aug;49(8):1643-60. doi: 10.1016/j.fct.2011.03.049. Epub 2011 Mar 30
A tiered approach to systemic toxicity testing for agricultural chemical safety assessment.
Doe JE, et al. Crit Rev Toxicol. 2006 Jan;36(1):37-68.
A proposed framework for assessing risk from less-than-lifetime exposures to carcinogens.
Felter SP et al.
Crit Rev Toxicol. 2011 Jul;41(6):507-44. doi: 10.3109/10408444.2011.552063. Epub 2011 May 18
Risk assessment in the 21st century: roadmap and matrix.
Embry MR et al. Crit Rev Toxicol. 2014 Aug;44 Suppl 3:6-16. doi: 10.3109/10408444.2014.931924.
The use of mode of action information in risk assessment: quantitative key events/dose-response framework for modeling the dose-response for key events.
Simon TW et al. Crit Rev Toxicol. 2014 Aug;44 Suppl 3:17-43. doi: 10.3109/10408444.2014.931925.
Regulatory assessment of chemical mixtures: Requirements, current approaches and future perspectives.
Kienzler A, Bopp SK, van der Linden S, Berggren E, Worth A.
Regul Toxicol Pharmacol. 2016 Oct;80:321-34. doi: 10.1016/j.yrtph.2016.05.020. Epub 2016 May 20
Assessment methods and Criteria
The examination generally consists of a written test, with open questions and the discussion of a case-study covering one of the topics of the course.
BIO/14 - PHARMACOLOGY - University credits: 7
Tutorials: 16 hours
Lectures: 48 hours
Lectures: 48 hours
Professor:
Marinovich Marina
Educational website(s)
Professor(s)